The present invention relates to yohimbine dimer compounds, pharmaceutical compositions containing such compounds, methods of making such compounds, as well as various uses thereof.
The initial classification of adrenergic receptors (AR""s) into xcex1- and xcex2-families was first described by Ahlquist in 1948 (Ahlquist RP, xe2x80x9cA Study of the Adrenergic Receptors,xe2x80x9d Am. J. Physiol. 153:586-600 (1948)). Functionally, the xcex1-ARs were shown to be associated with most of the excitatory functions (vasoconstriction, stimulation of the uterus and pupil dilation) and inhibition of the intestine. On the other hand, xcex2-ARs were implicated in vasodilation, bronchodilation and myocardial stimulation (Lands et al., xe2x80x9cDifferentiation of Receptor Systems Activated by Sympathomimetic amines,xe2x80x9d Nature 214:597-598 (1967)). Since this early work, xcex1-ARs have been subdivided into xcex11- and xcex12-AR. Cloning and expression of xcex1-AR have confirmed the presence of multiple subtypes of both xcex11-(xcex11a, xcex11b, xcex11d) and xcex12-(xcex12a, xcex12b, xcex12c) AR (Michel et al., xe2x80x9cClassification of xcex11-Adrenoceptor Subtypes,xe2x80x9d Naunyn-Schmiedeberg""s Arch. Pharmacol, 352:1-10 (1995); Macdonald et al., xe2x80x9cGene Targetingxe2x80x94Homing in on xcex12-Adrenoceptor-Subtype Function,xe2x80x9d TIPS, 18:211-219 (1997)).
In humans, the three xcex12-AR subtypes are encoded by distinct genes localized in different chromosomes. The xcex12a-AR gene is located in chromosome 10, while the xcex12b-AR gene is found on chromosome 2 and the xcex12c-AR gene on chromosome 4 (Bylund et al., xe2x80x9cInternational Union of Pharmacology Nomenclature of Adrenoceptors,xe2x80x9d Pharmacol. Rev., 46:121-142 (1994)).
Current therapeutic uses of xcex12-ARs drugs involve the ability of those drugs to mediate many of the physiological actions of the endogenous catecholamines and there are many drugs that act on these receptors to control hypertension, analgesia, anesthesia, and ocular and nasal congestion.
xcex12-ARs are found in the rostral ventrolateral medulla, and are known to respond to the neurotransmitter norepinephrine and the antihypertensive drug clonidine to decrease sympathetic outflow and reduce arterial blood pressure (Bousquet et al., xe2x80x9cRole of the Ventral Surface of the Brain Stem in the Hypothesive Action of Clonidine,xe2x80x9d Eur. J. Pharmacol., 34:151-156 (1975); Bousquet et al., xe2x80x9cImidazoline Receptors: From Basic Concepts to Recent Developments,xe2x80x9d 26:S1-S6 (1995)). Clonidine and other imidazolines also bind to imidazoline receptors (formerly called imidazoline-guanidinium receptive sites or IGRS) (Bousquet et al., xe2x80x9cImidazoline Receptors: From Basic Concepts to Recent Developments,xe2x80x9d 26:S1-S6 (1995)). Some researchers have speculated that the central and peripheral effects of imidazolines as hypotensive agents may be related to imidazoline receptors (Bousquet et al., xe2x80x9cImidazoline Receptors: From Basic Concepts to Recent Developments,xe2x80x9d 26:S1-S6 (1995); Reis et al., xe2x80x9cThe Imidazoline Receptor: Pharmacology, Functions, Ligands, and Relevance to Biology and Medicine,xe2x80x9d Ann. N.Y. Acad. Sci., 763:1-703 (1995); Diamant et al., xe2x80x9cImidazoline Binding Sites in Human Placenta: Evidence for Heterogeneity and a Search for Physiological Function,xe2x80x9d Br. J. Pharmacol., 106:101-108 (1992); Ragunathan et al., xe2x80x9cImidazoline Receptors and Their Endogenous Ligands,xe2x80x9d Annu. Rev. Pharmacol. Toxicol., 36:511-544 (1996); Miralles et al., xe2x80x9cDiscrimination and Pharmacological Characterization of I2-Imidazoline Sites with [3H]idazoxan and Alpha-2-Adrenoceptors [3H]RX821002 (2 Methoxy Idazoxan) in Human and Rat Brains,xe2x80x9d J. Pharmacol. Exp. Ther., 264:1187-1197 (1993)). The pharmacological profiles of drugs acting on imidazoline receptors have resulted in their classification into two main types: I1- and I2-imidazoline binding sites (Diamant et al., xe2x80x9cImidazoline Binding Sites in Human Placenta: Evidence for Heterogeneity and a Search for Physiological Function,xe2x80x9d Br. J. Pharmacol., 106:101-108 (1992); Miralles et al., xe2x80x9cDiscrimination and Pharmacological Characterization of I2-Imidazoline Sites with [3H]idazoxan and Alpha-2-Adrenoceptors [3H]RX821002 (2 Methoxy Idazoxan) in Human and Rat Brains,xe2x80x9d J. Pharmacol. Exp. Ther., 264:1187-1197 (1993); Olmos et al., xe2x80x9cPharmacological and Molecular Discrimination of Brain I2-Imidazoline Receptor Subtypes,xe2x80x9d Naunyn-Schmiedberg""s Arch. Pharmacol., 354:709-716 (1996)).
Yohimbine is a known potent and selective xcex12-AR antagonist, and has been used extensively as a pharmacological probe for studying the xcex12-AR (Starke K., Rev. Physiol. Biochem. Pharmacol, 88, 199 (1981)). Yohimbine, an indole alkaloid isolated from Pausinystlia yohimbe bark and Rauwolfia roots, is an xcex12-antagonist selective for xcex12 over xcex11 adrenoreceptors, but is also a serotonic antagonist. It has actions both in the central nervous system and in the periphery inducing hypertension and increases heart rate. Yohimbine has been used to treat male impotence and posturalo hypotension. It has also been used in research to induce anxiety (Foye et al. Principles of Medicinal Chemistry, Fourth Edition, Williams and Wilkins (1995), page 359). However, yohimbine does not show selectivity among three xcex12-AR subtypes (Hieble et al., J. Med. Chem., 38, 3415 (1995); Hieble et al., Prog. Drug Res., 47, 81 (1996)).
Although there have been a number of xcex12-AR antagonists identified (Ruffolo et al., J. Med. Chem., 38, 3681 (1995); Clark et al., Prog. Med. Chem., 23, 1 (1986)), only a small set of compounds have been reported that have a varied degree of selectivity among the three subtypes of xcex12-AR. However, these latter compounds suffer from either low subtype selectivity or binding to receptor sites outside the xcex12-AR subfamily (Ruffolo et al., J. Med. Chem., 38, 3681 (1995; Yound et al, Eur. J. Pharmacol., 168, 381 (1989); Devedjian et al, Eur. J. Pharmacol., 252, 43 (1994); Meana et al., Eur. J. Pharmacol., 312, 385 (1996); Beeley et al., Bioorg. Med. Chem., 3, 1693 (1995); Michel et al., Br. J. Pharmacol., 99, 560 (1990); Uhlen et al., Pharmacol. Exp. Ther., 271, 1558 (1994); Blaxall et al., Pharmacol. Exp. Ther., 259, 353 (1991); Bylund et al., Mol. Pharmacol., 42, 1 (1992); Okumura et al, Gen. Pharmacol., 19, 463 (1988)). Thus, a need exists to identify compounds which bind xcex12-AR subtypes with sufficient affinity and selectivity.
The present invention is directed to overcoming these and other problems encountered in the art.
The present invention relates to a compound according to formula (I): 
wherein R is a linker molecule, preferably having a length of about 2.5 xc3x85 to about 45 xc3x85.
The present invention also relates to a compound according to formula (I), wherein R (i.e., as a linker molecule) is a straight or branched chain alkyl, alkenyl, alkynyl comprising at least 2 carbon atoms in a main chain thereof; wherein R (i.e., as a linker molecule) is a straight or branched chain alkyl, alkenyl, alkynyl comprising at least 2 carbon atoms in a main chain thereof and an X group within the main chain and/or a Y group as a substituent linked to a carbon atom in the main chain with X being xe2x80x94Oxe2x80x94, carbonyl, xe2x80x94NR1xe2x80x94 with R1 being H or an alkyl, C(O)NHR1xe2x80x94 with R1 being an alkyl, xe2x80x94Sxe2x80x94, sulfoxide, sulfonyl, or a cyclic or multicyclic ring with or without heteroatoms as ring members and including, optionally, one or more substitutions on the ring structure(s), and with Y being xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)H, xe2x80x94SH, or a primary, secondary, or tertiary amine, a carboxylic acid, an ester, a keto group, xe2x80x94SO2NH2, or xe2x80x94SO2NHR2 with R2 being an alkyl; or wherein R (i.e., as a linker molecule) is a cyclic or multicyclic ring with or without hetero atoms as ring members and including, optionally, one or more substitutions on the ring structure(s).
The present invention also relates to a pharmaceutical composition, which includes a yohimbine dimer of the present invention and a pharmaceutically acceptable carrier.
The present invention further relates to a method of making a yohimbine dimer of the present invention, which includes reacting yohimbic acid with a di-amine according to the formula H2Nxe2x80x94Rxe2x80x94NH2 under conditions effective to yield a yohimbine dimer of the present invention.
Yet another aspect of the present invention relates to a method of treating or preventing an xcex12 adrenergic receptor mediated condition or disorder which includes: administering to a patient an effective amount of a yohimbine dimer of the present invention under conditions effective to treat or prevent the xcex12 adrenergic receptor mediated condition or disorder.
A further aspect of the present invention relates to a method of modulating the activity of an xcex12a adrenergic receptor which includes: contacting an xcex12a adrenergic receptor with a yohimbine dimer of the present invention under conditions effective to modulate the activity of the xcex12a adrenergic receptor.
A still further aspect of the present invention relates to a method of modulating the activity of an xcex12c adrenergic receptor which includes: contacting an xcex12c adrenergic receptor with a yohimbine dimer of the present invention under conditions effective to modulate the activity of the xcex12c adrenergic receptor.
The present invention provides additional advantages because it identifies a bivalent ligand approach to identify xcex12-AR subtype-selective antagonists. As demonstrated herein, the bivalent yohimbine ligands exhibit a higher degree of potency, binding affinity, and selectivity than their monovalent counterparts.